c-Fos (green) is more stable (top to bottom) in PDGF-treated cells.

Blenis/Macmillan

Duration of kinase signaling determines how a cell responds to external cues like growth factors. But how a cell measures signaling time has been a mystery. Now, Leon Murphy, John Blenis (Harvard Medical School, Boston, MA), and colleagues have found that immediate early gene (IEG) products have a sensor mechanism that makes these distinctions. Their findings may provide a target for cancer treatment drugs.

Growth factors PDGF and EGF elicit different responses in fibroblasts, with only PDGF inducing cells to enter S-phase. The group found that EGF transiently activated ERK MAP kinases, whereas PDGF stimulated prolonged activation. The IEG product c-Fos is known to be transcribed with similar kinetics in response to either growth factor, but c-Fos was only phosphorylated when ERK activity was sustained. This not only stabilized c-Fos, but also primed it for further phosphorylation by revealing a DEF domain, an ERK-docking motif. Without secondary phosphorylation, c-Fos was less able to promote cellular transformation.

“Since several other IEGs also have DEF domains,” says Blenis, “this group of IEGs may act as molecular sensors in many processes,” including neuronal differentiation and the generation of an immune response. Blenis and Murphy hope it will be possible to antagonize these sensors to block specifically ERK-regulated proliferation, such as that seen in Ras-induced cancers, thus possibly avoiding toxic side effects caused by disturbing ERK's other homeostatic cellular functions. ▪

Reference:

Murphy, L., et al. 2002. Nat. Cell Biol. 10.1038/ncb822.